SMC4 is a hypoxia-responsive driver of pulmonary arterial hypertension through an HIF-1α–HDAC6–p21 regulatory axis

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by aberrant vascular remodeling driven in part by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the molecular determinants underlying this cancer-like phenotype remain incompletely defined. METHODS AND RESULTS: Genomic analysis of patients with PAH revealed a significant upregulation of structural maintenance of chromosomes 4 (SMC4). In hypoxia-exposed mouse models and human PASMCs, SMC4 expression was similarly increased and localized primarily to the vascular smooth muscle layer. Functional studies demonstrated that SMC4 knockdown suppressed, whereas SMC4 overexpression enhanced, microtubule organization, cell-cycle progression, and PASMCs proliferation. Mechanistically, chromatin immunoprecipitation confirmed direct binding of HIF-1α to the SMC4 promoter, promoting its transcription under hypoxia. Co-immunoprecipitation further showed that SMC4 recruited histone deacetylase 6 (HDAC6) to repress the cyclin-dependent kinase inhibitor P21, thereby sustaining proliferative signaling. In vivo, partial genetic deficiency of SMC4 mitigated pulmonary vascular remodeling, reduced right ventricular hypertrophy, and improved hemodynamic parameters in hypoxia-induced PAH mice. CONCLUSIONS: SMC4 is a key regulator of PASMCs proliferation and pulmonary vascular remodeling through an HIF-1α-SMC4-HDAC6-P21 signaling axis. Modulation of this pathway may offer a potential therapeutic approach for PAH.